The antibody response of infants to vaccines is reduced compared to that of older children, including for T- dependent neoantigens, a response that requires the activation and differentiation of antigenically-naiveCD4 T cells and B cells into T follicular helper cells (TFh) and antibody-secreting plasma cells, respectively. We hypothesize that impaired infant vaccine immunogenicity is due, in part, to nave lymphocyte intrinsic mechanisms that include: 1) the predominance during infancy of newly-produced transitional-type CD4 T cells and B cells that have a reduced capacity for effector function; 2) the presence in neonates and infants of nave lymphocytes that retain a fetal program of maturational arrest and/or hematopoietic stem cell (HSC)-derived tolerance. To test these hypotheses, a set of cytometric features (Aim 1) and molecular features [mRNA expression and DNA methylation (Aim 2)] involved in the acquisition of TFh and B-cell effector function will be developed that robustly distinguishes neonatal nave lymphocytes from their adult counterparts. We expect that this neonatal signature will be shared with immature CD4 T-lineage and B-lineage precursor cells (i.e., CD4+CD8- thymocytes and immature B cells of the bone marrow, respectively), reflecting a state of maturational arrest, and with fetal CD4 T cells and B cells, reflecting a persistent fetal HSC differentiation program. We expect that both maturational arrest and the post-natal retention of a fetal HSC program will contribute to reduced immune function in the infant. Aim 3 will longitudinally study a group of infants and young children from The Gambia to determine the relationship between vaccine immunogenicity and normal vs. malnutrition-related perturbation of the post-natal maturation of nave lymphocytes. We hypothesize that fetal malnutrition will epigenetically reprogram the adaptive immune system for premature immune senescence and impaired vaccine immunogenicity. This will be tested by determining the relationship of vaccine immunogenicity with nave lymphocyte phenotype/function, mRNA expression, DNA methylation, and cell homeostasis in infants who have or have not experienced pre-natal nutritional stress. Together, these studies will substantially enhance our understanding of the normal process of post-natal maturation of the naiveCD4 T-cell and B-cell compartments, their influence on vaccine immunogenicity, and their perturbation by prenatal nutritional stress. They may also point out approaches by which infant immune responses could be enhanced by nutritional intervention in early life or by therapeutic expansion of the nave lymphocyte compartment. PUBLIC HEALTH RELEVANCE: The infant does not respond to vaccines as well as older children and adults, and, as a consequence, is more vulnerable to infections. This research will determine why two types of blood cells that work together to make a vaccine response - the CD4 T cell and the B cell - are not as effective in the infant as in older children and adults. The importance of malnutrition during pregnancy on the infant's CD4 T-cell and B-cell function and the vaccine response will also be studied in a group of infants from The Gambia, a less developed African country. This research will determine ways in which the infant vaccine response could be improved by nutritional supplements early in life or by using drugs that boost the function of CD4 T cells or B cells.